Mitochondria form contact sites with the nucleus to couple pro-survival retrograde response

Desai, R; East, D A; Hardy, L; Crosby, J; Rigon, M; Faccenda, D; Alvarez, M S; Singh, A; Mainenti, M; Hussey, L K; Bentham, R; Szabadkai, G; Zappulli, V; Dhoot, G; Romano, L E; Dong, X; Coppens, I; Hamacher-Brady, A; Chapple, J P; Abeti, R; Fleck, R A; Vizcay-Barrena, G; Smith, K; Campanella, M

Abstract

Mitochondria drive cellular adaptation to stress by retro-communicating with the nucleus. This process is known as Mitochondrial Retrograde Response (MRR) and is induced by mitochondrial dysfunctions. MRR results in the nuclear stabilization of pro-survival transcription factors such as the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). Here we demonstrate that MRR is facilitated by contact sites between mitochondria and the nucleus. The 18kD Translocator Protein (TSPO), which de-ubiquitylates and stabilizes the mitochondria thereby preventing their mitophagy-mediated segregation, is required for this interaction. The tethering TSPO enacts is mediated by the complex formed with the Protein kinase A (PKA) via the A-kinase anchoring protein Acyl-CoA Binding Domain Containing 3 (ACBD3) and allows the redistribution of cholesterol which sustains the pro-survival response by blocking NF-kB de-acetylation. This work proposes a new paradigm in the mitochondrial retro-communication by revealing the existence of contact sites between mitochondria and the nucleus and a signalling role for cholesterol.

Citation

Desai, R., East, D. A., Hardy, L., Crosby, J., Rigon, M., Faccenda, D., …Campanella, M. (in press). Mitochondria form contact sites with the nucleus to couple pro-survival retrograde response. Science Advances, https://doi.org/10.1101/445411

• Journal Article Type: Article
• Acceptance Date: Nov 17, 2020
• Online Publication Date: Dec 18, 2020
• Deposit Date: Nov 19, 2020
• Publicly Available Date: Sep 29, 2021
• Journal: Science Advances
• Publisher: American Association for the Advancement of Science
• Peer Reviewed: Peer Reviewed
• Book Title: Mitochondria form contact sites with the nucleus to couple pro-survival retrograde response
• DOI: https://doi.org/10.1101/445411
• Public URL: https://rvc-repository.worktribe.com/output/1374825
• Publisher URL: https://doi.org/10.1101/445411